The voltage-gated sodium channel is an integral component of impulse conduction by neuronal cells, transmitting the initial inward current during an action potential. The channel consists of one large subunit termed alpha that is associated in some tissues with one or two small subunits termed beta. There are multiple different isoforms of the alpha subunit, including at least 4 distinct forms in the central nervous system (CNS). The physiological significance of the different forms is not known. The overall objective of this research is to determine the importance of the different channel isoforms in the CNS. There are two major goals. The first aspect is to define the mechanism and physiological significance in the CNS of sodium channel inactivation. We have previously shown that the cytoplasmic linker between domains III and IV is critical for sodium channel inactivation, possibly forming the nucleus of an inactivating particle. We will examine the mechanism and physiological significance of sodium channel inactivation by testing three hypotheses. First, we will determine if the III-IV linker binds to the III S4-S5 region as an inactivating particle. Second, we will determine if incomplete inactivation of sodium channels in the CNS lead to epilepsy. Third, we will determine if local anesthetics bind to the same region of the channel that serves as the docking site for the inactivating particle. The second major goal of these studies is to determine the significance of the different sodium channel isoforms in the CNS by testing two hypotheses. First, we will determine if two different isoforms are localized in different regions of the axon because of specific amino acid sequences in the cytoplasmic linkers. Second, we will determine if rBl and Na6 channels mediate the transient and maintained currents in cerebellar Purkinje cells, respectively. These studies should enhance our knowledge concerning the normal function of the voltage-gated sodium channel in the CNS, ultimately helping to provide an understanding of the pathological processes that affect channel function in disease and to design pharmaceuticals that interact with channels of specific tissues.